Although many successful vaccination regimens have either eliminated or completely controlled infectious diseases, such as smallpox and polio, it has become apparent that certain pathogens are not readily controlled by current vaccination approaches. For instance, pathogens such as HIV, Mycobacterium tuberculosis and the malaria parasite all resist the humoral immunity that is characteristically generated by traditional vaccines. Significant effort has gone into developing vaccines that can promote potent cellular immunity to these and related pathogens. Similarly, immunization with tumor antigens primarily depends on T cells, especially CD8+ CTL, to recognize and destroy cancer cells because many tumor-associated antigens are intracellular proteins. The induction of cellular immunity, however, is complex and poses substantial problems for vaccinologists. These include difficulties in generating cellular immunity that is of sufficient strength and longevity.
One potential approach to circumvent these problems is through the sequential administration of vaccines using heterologous vectors. Although a typical prime-boost regimen involves DNA- and vaccinia-based vaccines, other combinations using bacteria-virus or two different viruses has also been explored in animal models. The most used poxvirus for vaccination is vaccinia virus, which was used for vaccination against smallpox. Recombinant vaccinia can deliver foreign antigens to the cytoplasm of mammalian cells, thereby allowing them direct access to antigen processing pathways which leads to presentation of antigen-derived peptides in association with MHC Class I and Class II molecules on the cell surface. This property makes vaccinia useful as a recombinant vaccine, particularly for stimulating CD 8+ and CD4+ T cell immune responses. Concern about the capacity of vaccinia virus to replicate in mammalian cells has limited its clinical use and led to the search for safer alternatives.
With respect to the use of viruses to treat disease such as cancer, oncolytic viruses (OV) have been found to cure cancer in animal models if they infect tumors and replicate extensively to mediate complete destruction. However, broad clinical application requires treating immunocompetent hosts bearing malignancies that may have partially intact antiviral mechanisms. An active host immune response against the virus that rapidly eliminates viral replication, leading to incomplete or transient tumor destruction represents an important barrier to success. It has been shown in naïve animals that the development of an acquired immune response usually takes less than a week, leaving a small window of opportunity for oncolytic vectors to function. To maximize replication of the administered virus or re-administered virus, a variety of approaches have been tested ranging from outright immunosuppression, to the use of carrier cells (so-called “Trojan horses”) and viral cloaking.
Despite the foregoing attempts to address the problems associated with current methods of vaccination, it is desirable to develop more effective methods of generating an immune response in a mammal.